Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations.

AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.

6-Substituted 2,2-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers.

In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-ben zopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol.

Pharmacological evidence that inducible nitric oxide synthase is a mediator of delayed preconditioning.

Brief periods of myocardial ischaemia preceding a subsequent more prolonged ischaemic period 24-72 h later confer protection against myocardial infarction ('delayed preconditioning' or the 'second window' of preconditioning). In the present study, we examined the effects of pharmacological modifiers of inducible nitric oxide synthase (iNOS) induction and activity on delayed protection conferred by ischaemic preconditioning 48 h later in an anaesthetized rabbit model of myocardial infarction. Rabbits underwent a myocardial preconditioning protocol (four 5 min coronary artery occlusions) or were sham-operated. Forty-eight hours later they were subjected to a sustained 30 min coronary occlusion and 120 min reperfusion. Infarct size was determined with triphenyltetrazolium staining. In rabbits receiving no pharmacological intervention, the percentage of myocardium infarcted within the risk zone was 43.9+5.0% in sham-operated animals and this was significantly reduced 48 h after ischaemic preconditioning with four 5 min coronary occlusions to 18.5+5.6% (P<0.01). Administration of the iNOS expression inhibitor dexamethasone (4 mg kg(-1) i.v) 60 min before ischaemic preconditioning completely blocked the infarct-limiting effect of ischaemic preconditioning (infarct size 48.6+/-6.1%). Furthermore, administration of aminoguanidine (300 mg kg(-1), s.c.), a relatively selective inhibitor of iNOS activity, 60 min before sustained ischaemia also abolished the delayed protection afforded by ischaemic preconditioning (infarct size 40.0+/-6.0%). Neither aminoguanidine nor dexamethasone per se had significant effect on myocardial infarct size. Myocardial risk zone volume during coronary ligation, a primary determinant of infarct size in this non-collateralized species, was not significantly different between intervention groups. There were no differences in systolic blood pressure, heart rate, arterial blood pH or rectal temperature between groups throughout the experimental period. These data provide pharmacological evidence that the induction of iNOS, following brief periods of coronary occlusion, is associated with increased myocardial tolerance to infarction 48 h later.

Synthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openers.

The synthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openers are described. These (2-fluoromethyl) derivatives displayed smooth muscle relaxant activities comparable to or more potent than the corresponding 2-methyl analogues.

Myocardial protection afforded by nicorandil and ischaemic preconditioning in a rabbit infarct model in vivo.

We previously showed that preoperative nicorandil, a hybrid potassium channel opener and nitrate compound, conferred cardioprotective effects in a hypoxia/reoxygenation model of isolated human atrial muscle by using functional recovery as an end point, and that ischaemic preconditioning surprisingly abolished the protection afforded by nicorandil. In view of this paradoxic result, this study was undertaken to assess whether ischaemic preconditioning influences any protective effect of nicorandil by using infarct size as an end point. In addition, we investigated the underlying mechanisms of the protective action of nicorandil. Rabbits underwent a midline sternotomy under anaesthesia. A left coronary branch was occluded for 30 min followed by 120 min of reperfusion. Nicorandil (100 microg/kg bolus + 10 microg/kg/min) was given intravenously 30 min before coronary occlusion and continued to the time of reperfusion (early treatment) or 5 min before reperfusion and continued throughout reperfusion (late treatment). Ischaemic preconditioning was achieved by a single episode of 5-min coronary occlusion followed by 10-min reperfusion before the 30-minute occlusion in the presence or absence of nicorandil. Risk volume and infarct volume were determined by fluorescent microspheres and tetrazolium staining, respectively. Early treatment with nicorandil conferred a significant decrease in percentage of infarct size within the risk zone (24.9 +/- 2.9%) when compared with control (39.2 +/- 4.3%; p < 0.01). Late treatment with nicorandil had no effect on infarct size (43.5 +/- 3.4%). Ischaemic preconditioning also resulted in significant reduction in infarct size (13.4 +/- 4.3%; p < 0.01 vs. control). The combination of ischaemic preconditioning with nicorandil (early treatment) showed an intermediate protective efficacy between early treatment with nicorandil alone and ischaemic preconditioning alone (18.1 +/- 4.2%; p < 0.01 vs. control). Nitroglycerin (10 microg/kg bolus + 1 microg/kg/kg/min, i.v.) given before and during ischaemia tended to reduce infarct size, but the effect was not statistically significant (28.9 +/- 2.9%; p > 0.05 vs. control). Although an adenosine triphosphate (ATP)-sensitive potassium channel blocker, 5-hydroxydecanoate (5 mg/kg, i.v.) by itself had no effect on infarct size (38.8 +/- 3.6%), the protective effect of nicorandil was abolished by 5-hydroxydecanoate (37.7 +/- 5.8%; p < 0.05 vs. early treatment of nicorandil). There were no differences in area at risk or haemodynamics between groups. Our results show that nicorandil has a protective effect against myocardial infarction in our rabbit model when infused before and during ischaemia, but not during reperfusion, and the protective effect is abolished by an ATP-sensitive potassium channel blocker. Furthermore, the addition of ischaemic preconditioning does not detrimentally influence the effect of nicorandil. This suggests that nicorandil can confer an infarct-limiting effect by opening of ATP-sensitive potassium channels with or without intermittent ischaemia, as may happen in patients with unstable angina.

Genistein, a tyrosine kinase inhibitor, blocks the "second window of protection" 48 h after ischemic preconditioning in the rabbit.

We have previously reported a delayed or "second window of protection" against infarction 24-72 h after ischemic preconditioning in the rabbit. This phenomenon has also been associated with the protein kinase C signalling pathway. In the present study, we expanded our investigation to ascertain whether protein tyrosine kinase was in any way associated with this phenomenon in the rabbit heart. We found that 48 h after ischemic preconditioning with 4x5 min coronary occlusions the percentage of myocardium infarcting within the risk zone following a 30-min coronary occlusion and 120-min reperfusion (I/R) was reduced from 39. 6+/-3.3% to 18.0+/-3.7% (P<0.01). However, an i.v. bolus administration of genistein (5 mg/kg), a tyrosine kinase inhibitor, 5 min before ischemic preconditioning stimulus, abolished this protection (I/R=39.0+/-3.4%). Genistein per se had no significant effect on infarction 48 h later. Risk zone volume after coronary ligation was not significantly different between intervention groups. There were no differences in hemodynamic parameters between groups throughout the experimental period. We conclude that the second window of protection, 48 h after preconditioning, is mediated by tyrosine kinase activation in the rabbit heart.

Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim.

1. The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol-induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea-pig and human airway smooth muscles. 2. In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration-dependent relaxation of the carbachol-induced contraction. The IC50 values were 0.35 microM (pIC50: 6.46 +/- 0.10, n = 9) and 0.55 microM (pIC50: 6.26 +/- 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 microM (pIC50: 6.73 +/- 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 microM). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03-1 microM) but not by charybdotoxin (100 nM). 3. Levcromakalim (1 microM) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 microM) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4. Levcromakalim (10 microM) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 microM) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 microM) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5. Both KC 128 and levcromakalim relaxed the guinea-pig isolated tracheal smooth muscles precontracted by carbachol (100 nM), histamine (3 micro M) or U46619 (10 nM). KC 128 was approximately 10 times more potent than levcromakalim for each agonist.6. In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentration dependent relaxation of the carbachol-induced contraction.7. It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea-pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles.On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues.These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener- and glyburide-sensitive K+ channels are present in the dog airway smooth muscles.

In vivo bronchodilator action of a novel K+ channel opener, KC 399, in the guinea pig.

We evaluated the in vivo bronchodilator effects of KC 399, a novel K+ channel opener. In anesthetized guinea pigs, i.v. administration of KC 399 (1-10 micrograms/kg), BRL38227 (lemakalim, 10-100 micrograms/kg) and salbutamol (0.3-3 microgram/kg) evoked a dose-related reduction in the histamine-induced bronchoconstriction. The dose of KC 399 producing a 50% inhibition of the bronchoconstriction induced by histamine was 2.6 (1.9-3.6) microgram/kg. In exerting this action, KC 399 was approximately 13 times more potent than BRL38227, but approximately 4 times less potent than salbutamol. The bronchodilator action of i.v. KC 399 (10 micrograms/kg) lasted for over 30 min, whereas that induced by either BRL38227 (100 micrograms/kg) or salbutamol (3 micrograms/kg) lasted less than 10 min. When given by inhalation, KC 399 (1-30 micrograms/ml) induced a more prolonged effect and was a more potent bronchodilator than BRL38227 (0.3-1 mg/ml) in the histamine-induced bronchoconstriction model. Inhaled KC 399 (30 and 100 micrograms/ml) also prevented the antigen-induced bronchoconstriction in sensitized guinea pigs under anesthetic. When given by the oral route, KC 399, BRL38227 and salbutamol protected conscious guinea pigs from asphyxic collapse in response to inhaled histamine, their effective doses being 0.03, 1 and 3 mg/kg, respectively. From these in vivo experimental results, we conclude that KC 399 is an orally active, potent and long lasting bronchodilator.

The effect of a novel benzopyran derivative, KC 399, on the isolated guinea-pig trachealis and human bronchi.

1. In isolated guinea-pig trachealis, KC 399, BRL 38227 and salbutamol suppressed the spontaneously generated tone in a concentration-dependent manner with pD2 values of 8.89 +/- 0.09 (n = 14), 6.18 +/- 0.07 (n = 11) and 7.72 +/- 0.12 (n = 8), respectively. 2. The bronchodilator effects of KC 399 and BRL 38227 were antagonized by glibenclamide but not by charybdotoxin or apamin. The effect of salbutamol was antagonized by charybdotoxin but not by glibenclamide or apamin. 3. KC 399 and BRL 38227 failed to inhibit the tone evoked by 90 mM K+ in guinea-pig trachealis, whereas salbutamol did inhibit it, in a concentration-dependent manner. 4. These bronchodilators also relaxed the tone of isolated guinea-pig trachealis supported by histamine, carbachol, U46619 or leukotriene D4. Their order of potency was always KC 399 > salbutamol > BRL 38227. 5. KC 399 and BRL 38227 relaxed isolated human bronchi contracted with histamine or carbachol. 6. We conclude that KC 399 is a potent relaxant of isolated guinea-pig trachealis and human bronchi in vitro. The relaxant action of KC 399 could be due to the opening of glibenclamide-sensitive K+ channels.

Improvement of cardiac performance by pimobendan, a new cardiotonic drug, in the experimental failing dog heart.

The cardiotonic effect of pimobendan was studied in 6 dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. Pimobendan in doses of 1-10 mg improved cardiac function in a dose-dependent manner and at 10 mg improved it beyond the control. These doses of pimobendan, however, produced neither a significant increase in heart rate nor arrhythmias. The results indicate that the drug may be of use in the treatment of heart failure.

Spasmolytic action of nicorandil in canine conductive coronary arteries in vivo is not modified by glibenclamide.

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.

Differential modulation by beta adrenoceptors of inward calcium and delayed rectifier potassium current in single ventricular cells of guinea pig heart.

This study was designed to investigate the modulation of the high-threshold (L-type) inward calcium current (ICa) and the delayed rectifier potassium current (IK) by beta adrenoceptor stimulation in single ventricular cells of guinea pig heart. Single ventricular cells were prepared by the collagenase dispersion procedure, and membrane currents were recorded with a patch electrode by use of the whole-cell voltage clamp method. ICa was obtained by intra- and extracellular perfusion with the Cs(+)-solutions that suppressed potassium currents. IK was evaluated in Co+(+)-Tyrode's solution in which 0.9 mM Co+(+) was substituted for equimolar Ca+(+) to abolish ICa. Isoproterenol, a nonselective beta adrenoceptor agonist, increased not only ICa but also IK at the same threshold concentration (1 nM). In contrast, the threshold concentration of T-1583, a selective beta-1 adrenoceptor agonist, for increasing ICa (1 nM) was distinctly lower than that for increasing IK (100 nM). These results suggest that ICa and IK can be differentially modulated by beta adrenoceptors.

Functional evaluation of sympathetically mediated responses in in vivo lower urinary tract of dogs.

An in vivo procedure for evaluating local effects of alpha-adrenoceptor stimuli on the lower urinary tract was developed in anesthetized dogs. Electrical stimulation of hypogastric nerve at varied frequencies (1, 2, and 4 Hz) and intraarterial (i.a.) administration of an alpha 1-adrenoceptor agonist, phenylephrine (0.3, 1, and 3 micrograms) to the urethra and bladder through the cannulated right external iliac artery caused reproducible frequency- or dose-related increases in intraurethral pressure (IUP). Intrabladder pressure (IBP) was increased by the nerve stimulation but not by i.a. phenylephrine. Acetylcholine (10 micrograms) given i.a. elicited increases in both IUP and IBP. Prazosin (0.1, 1, and 10 micrograms/kg, i.v.) dose-dependently suppressed the urethral contractile responses to the nerve stimulation and i.a. phenylephrine, but it failed to affect the bladder contraction evoked by the nerve stimulation. The results suggest that the urethral contractile responses to hypogastric nerve stimulation as well as i.a. phenylephrine were mediated via alpha 1-adrenoceptors, whereas the IBP increasing effect of hypogastric nerve stimulation was not mediated via alpha 1-adrenoceptors.

In vivo experiments for the evaluation of alpha 1-adrenoceptor antagonistic effects of SGB-1534 on canine urethra.

The alpha 1-adrenoceptor blocking effects of SGB-1534 on the urethral smooth muscle were compared in in vivo lower urinary tract preparations of anesthetized dogs, with the effects of other alpha 1-adrenoceptor antagonists, prazosin and bunazosin. Hypogastric nerve stimulation and selective administration of phenylephrine to the urethra and bladder through the cannulated right external iliac artery (i.a.) elicited reproducible frequency- and dose-dependent increases in intra-urethral pressure. Intra-bladder pressure was increased by the nerve stimulation but not by i.a. phenylephrine. SGB-1534, prazosin or bunazosin (0.1-10 micrograms/kg i.v.) dose dependently suppressed the urethral contraction evoked by the nerve stimulation and i.a. phenylephrine but did not influence the bladder contraction elicited by nerve stimulation. The alpha 1-adrenoceptor blocking potency of SGB-1534 was approximately 2.3 and 8.1 times greater than that of prazosin and bunazosin, respectively. The results indicate that alpha 1-adrenoceptors may mediate mainly the urethral contraction induced by hypogastric nerve stimulation and i.a. phenylephrine, and that SGB-1534 was more potent alpha 1-adrenoceptor blocking activity than prazosin and bunazosin in the canine urethra.

Coronary vasodilator and cardiac effects of NKY-722, a novel hydrophilic 1,4-dihydropyridine derivative, in the blood-perfused dog heart.

The coronary vasodilator and cardiac effects of NKY-722, a novel hydrophilic 1,4-dihydropyridine derivative, were evaluated in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. NKY-722 was administered intraarterially. NKY-722 increased coronary blood flow in all preparations. In SA node preparations, NKY-722 reduced sinus rate and produced atrial standstill in large doses. The dose that produced a 15% (nearly half-maximum) decrease in sinus rate was about six times the dose that doubled coronary blood flow. In AV node preparations, NKY-722 prolonged AV conduction time and produced second- or third-degree AV block in large doses only when administered into the artery supplying the AV node. The dose that produced a 15% (nearly half-maximum) increase in AV conduction time was about 3.5 times the dose that doubled coronary blood flow. In paced papillary muscle preparations, NKY-722 reduced the force of contraction. However, the dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 100 times the dose that doubled coronary blood flow. In spontaneously beating papillary muscle preparations, NKY-722 failed to change the beating rate. The vasodilator effect of NKY-722 was of longer duration than the negative chronotropic, dromotropic, and inotropic effects. These results indicate that NKY-722 is highly vasoselective, and the cardiovascular profile of NKY-722 is essentially identical to that of currently available, lipophilic 1,4-dihydropyridine calcium antagonists.

Isolated dog hearts prepared in cold tyrode solution and reperfused with arterial blood are functionally and ultrastructurally normal.

Isolated dog whole heart preparations run by means of cross-circulation with support dogs were prepared in two different ways. In one way the donors' hearts were quickly removed, and cannulation of their major vessels, insertion of a latex balloon into the left ventricle, etc. were all done in cold Tyrode solution in the condition of heart-anoxia within 30 min and then reperfused with arterial blood of support dogs (Group A). In the other, cannulation of the major vessels of the donors' hearts were done in the state of "beating heart" (Group B). In these two kinds of preparations we compared basal cardio-coronary measurements (coronary blood flow, left ventricular pressure (LVP), its first derivative (LV dP/dt) and myocardial oxygen consumption (MVO2) and ultrastructure of the myocardium at various periods of the experiments. There were no significant differences in these cardio-coronary measurements and ultrastructural findings. Furthermore, Group A preparations kept stable levels of cardio-coronary measurements for 5 hr or more and responded normally to isoproterenol. Therefore, isolated, blood-perfused dog whole hearts prepared in cold Tyrode solution and reperfused by means of the cross-circulation method would be useful for physiological, pharmacological and biochemical studies.

Tissue angiotensin-converting enzyme blockade by MC-838 (altiopril calcium) infused intravenously to miniature pigs: comparison with captopril.

The effect of a new orally active angiotensin-converting enzyme (ACE) inhibitor, calcium(-)-N-[(S)-3-[(N-cyclohexyl-carbonyl-D-alanyl)thio]-2-methyl- prolinate (MC-838, altiopril calcium), on cardiohemodynamics and tissue ACE activity was compared with that of captopril in the anesthetized miniature pig. MC-838 and captopril were infused i.v. for 1 or 3 hr at an equimolar rate of 20 and 10 micrograms/kg.hr-1, respectively. When MC-838 was infused i.v., captopril appeared in approximately 40% of MC-838 in serum, indicating that the amount of serum captopril during the equimolar concentration treatment with MC-838 corresponds to half of serum captopril after the dosing of captopril. During the infusion, the drugs did not significantly affect systemic blood pressure (SBP), heart rate (HR), renal blood flow (RBF) and renal vascular resistance (RVR). MC-838 and captopril, in a similar degree, attenuated the vasoconstrictor response to angiotensin-I (A-I) injected into the renal artery (i.a.), and enhanced the vasodilator one to i.a. bradykinin, 3 hr after the onset of the drug infusion. The animals were sacrificed at 1 and 3 hr after the onset of the infusion of MC-838 or captopril, and the ACE activity in serum and some target organs (lung, kidney, heart, brain and aorta) was determined. Effective activities of MC-838 and captopril occurred in the lung and kidney (only at 3 hr for captopril) where higher ACE activity in a variety of tissues was found, to a lesser degree in the serum (only by captopril) and not at all in the brain, heart and aorta.

Comparison of cardiovascular effects of SGB-1534 and prazosin, selective alpha 1-adrenoceptor antagonists, in anesthetized dogs.

The cardiovascular effects of a novel antihypertensive agent, SGB-1534, and its alpha 1-adrenoceptor antagonism in the renal vasculature were investigated in anesthetized dogs and compared with those of prazosin. The doses of SGB-1534 (1-100 micrograms/kg) and prazosin (3-300 micrograms/kg) were increased by a factor of about 3 and given i.v. in a cumulative way. SGB-1534 produced dose-dependent decreases in systemic (systolic, mean and diastolic) blood pressure (SBP), left ventricular (LV) systolic and end-diastolic pressure, and femoral vascular resistance, accompanied by no changes in heart rate (HR), LVdP/dt max and pressure-rate product. Femoral blood flow tended to increase, but the change was not significant. Renal blood flow and the vascular resistance remained virtually unchanged. Similar results were obtained with prazosin for the cardiovascular parameters tested except diastolic SBP and femoral vascular resistance, in which no significant changes occurred. SGB-1534 and prazosin dose-dependently attenuated renal vasoconstrictor responses to a relatively selective alpha 1-adrenoceptor agonist, phenylephrine (3 or 10 micrograms) given into the renal artery. When the doses that attenuated the vasoconstrictor response to phenylephrine by 50% were compared on a weight basis, alpha 1-adrenoceptor antagonistic activity of SGB-1534 was approximately 25 times more potent than that of prazosin in the renal vasculature of dogs. Both alpha 1-adrenoceptor antagonists showed a significant positive correlation between the systemic hypotensive effects and the alpha 1-adrenoceptor antagonism in the renal vasculature. Thus, it seems that SGB-1534, like prazosin, has a balanced effect decreasing afterload as well as preload and that the hypotension is mainly due to the alpha 1-adrenoceptor antagonism in the peripheral vasculatures.

Cardiac and coronary vasodilator profile of pimobendan, a new cardiotonic drug, revealed by use of isolated, blood-perfused dog heart preparations.

Cardiac and coronary vasodilator effects of pimobendan (UD-CG 115 BS) were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Pimobendan was administered intra-arterially. In paced papillary muscle preparations, the drug increased the force of contraction in a dose-dependent manner. In SA node preparations, the drug produced an increase in sinus rate. When the drug was injected into the artery supplying the AV node, the drug produced a decrease in AV conduction time by accelerating AV nodal conduction in AV node preparations. In spontaneously beating papillary muscle preparations, the drug increased the rate of ventricular automaticity. No ventricular arrhythmias were produced by the drug. In all preparations, the drug increased (coronary) blood flow. The order of effectiveness of pimobendan on the above cardiovascular variables was as follows: ventricular muscle contraction much greater than coronary blood flow greater than SA nodal automaticity greater than AV nodal conduction greater than ventricular automaticity. The results indicate that pimobendan is relatively specific for force and its cardiovascular profile is very similar to those of phosphodiesterase inhibitors. Therefore, it is likely that this cardiovascular profile would be determined by its inhibitory action on phosphodiesterase.